Although Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens, the influence of polymorphisms in this gene family on susceptibility to infection in humans is poorly understood. We previously demonstrated that TLRS recognizes flagellin, a potent inflammatory stimulus present in the flagellar structure of many bacteria. We have also shown that approximately 10% of individuals have a TLRS stop codon polymorphism (TLR5-392STOP) that inhibits flagellin signaling in a dominant fashion and is associated with susceptibility to pneumonia caused by Legionella pneumophila, a flagellated bacterium. While these observations indicate that TLRS influences susceptibility to human infection, a number of critical issues are not understood, including the mechanism, scope, and nature of TLRS's influence on the immune response during the course of an in vivo infection. Our hypothesis is that alteration of TLRS, via polymorphisms in humans or targeted TLRS gene deletion in mice, will change the host response to flagellated bacteria at molecular, cellular, and in vivo levels. We aim to: 1) determine the novel molecular mechanism of TLR5-392STOP's dominant inhibition of flagellin signaling in humans, 2) use mouse knockout strains to understand the influence of TLRS on the in vivo immune response to infection with Legionella pneumophila, and 3) use murine transgenic and bone marrow chimera studies to examine which cells regulate TLRS-mediated immune responses to Legionella. The TLR5-392STOP mutation provides a unique opportunity to study the in vitro and in vivo effects of human TLRS deficiency and, along with TLRS-/- mice, will enable us to address critical questions in innate immunity of receptor redundancy, regulation, and specificity. The immunogenetic models derived from these studies will illuminate the molecular basis of why individuals have different susceptibility to flagellated bacterial infections and hopefully culminate in novel insights for future therapies.